Sirt3 Promotes the Urea Cycle and Fatty Acid Oxidation during Dietary Restriction

Hallows, William C.; Yu, Wei; Smith, Brian C.; Devries, Mark K.; Ellinger, James J.; Someya, Shinichi; Shortreed, Michael R.; Prolla, Tomas A.; Markley, John L.; Smith, Lloyd M.; Zhao, Shimin; Guan, Kun‐Liang; Denu, John M.

doi:10.1016/j.molcel.2011.02.001

Cited by 63 publications

(86 citation statements)

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“…Under fasting conditions, SIRT3-deficient mice show decreased fatty acid b-oxidation, resulting in elevated serum long-chain fatty acid levels (54,58). Inefficient fatty acid oxidation may contribute to the reduced ATP levels of SIRT3-deficient mice under fasting conditions (1).…”

Section: Sirt3 Promotes Fatty Acid Oxidationmentioning

confidence: 99%

“…Using a high-throughput approach combining acetylpeptide arrays with metabolomics analysis, Hallows et al identified ornithine transcarbamoylase (OTC) as a SIRT3 substrate (54). OTC is an enzyme that catalyzes the second step of the urea cycle, the key process in the detoxification of ammonia generated by amino-acid catabolism.…”

Section: Sirt3 Regulates the Urea Cycle Via Ornithine Transcarbamoylamentioning

confidence: 99%

“…OTC is an enzyme that catalyzes the second step of the urea cycle, the key process in the detoxification of ammonia generated by amino-acid catabolism. SIRT3 directly deacetylates OTC at lysine 88 and stimulates its activity, thus promoting urea cycle function (54). As a consequence, SIRT3-deficient mice display an inability to deacetylate and activate mitochondrial OTC, and show urea cycle functional deficiency in response to CR along with elevated urinary orotic acid levels (54), a well-known clinical marker of human OTC deficiency (38).…”

Section: Sirt3 Regulates the Urea Cycle Via Ornithine Transcarbamoylamentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

132

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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Section: Sirt3 Promotes Fatty Acid Oxidationmentioning

confidence: 99%

Section: Sirt3 Regulates the Urea Cycle Via Ornithine Transcarbamoylamentioning

confidence: 99%

Section: Sirt3 Regulates the Urea Cycle Via Ornithine Transcarbamoylamentioning

confidence: 99%

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Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

132

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“…Furthermore, SIRT3 is involved in fatty acid oxidation in the liver (Giralt and Villarroya, 2012). This was supported by evidence in SIRT3-knockout mice demonstrating increased palmitoylcarnitine and triacylglycerols in the liver and various acylcarnitines in the blood (Hallows et al, 2011;Hirschey et al, 2010). SIRT3 is also expressed abundantly in the heart, and its overexpression is protective against cardiac hypertrophy, while SIRT3 depletion enhances susceptibility to hypertrophy (Sundaresan et al, 2009).…”

Section: Sirt3mentioning

confidence: 90%

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

Park

Mori

Shimokawa

2013

Molecules and Cells

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Sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, are emerging as key molecules that regulate aging and age-related diseases including cancers, metabolic disorders, and neurodegenerative diseases. Seven isoforms of SIRT (SIRT1-7) have been identified in mammals. SIRT1 and 6, mainly localized in the nucleus, regulate transcription of genes and DNA repair. SIRT3 in the mitochondria regulates mitochondrial bioenergetics. Initial studies in yeasts, nematodes, and flies indicated a strong connection of SIRT with the life-prolonging effects of calorie restriction (CR), a robust experimental intervention for longevity in a range of organisms. However, subsequent studies reported controversial findings regarding SIRT roles in the effect of CR. This review describes the functional roles of mammalian SIRTs and discusses their relevance to mechanisms underlying the longevity effect of CR.

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“…Here SIRT3 deacetylates and activates long-chain acylCoA dehydrogenase and medium-chain acyl-CoA dehydrogenase (MCAD) 3 (5,6). In parallel, under dietary restricted conditions, multiple fatty acid oxidation enzymes show increased lysine residue deacetylation in control versus SIRT3 knockout mice, and SIRT3 null mice have increased accumula-tion of acylcarnitines, a finding consistent with reduced fat oxidation (7). On the other hand, in response to fat feeding, the acetylation of ␤-hydroxyacyl CoA dehydrogenase results in activation of enzyme activity in muscle cells (8).…”

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confidence: 85%

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

Chen

Aponte

et al. 2015

Journal of Biological Chemistry

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Background: A distinct mechanism linking fasting-associated mitochondrial protein acetylation and increased fat oxidation is unknown. Results: Acetylation of heat shock protein 10 enhances medium-chain acyl-CoA dehydrogenase folding, enzyme activity, and fat oxidation. Conclusion: A novel acetylation-dependent mechanism modulates fat oxidation via regulating mitochondrial metabolic enzyme folding. Significance: A Sirtuin 3 deacetylase-linked mechanism to control fat oxidation via modulation of enzyme folding has been identified.

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Sirt3 Promotes the Urea Cycle and Fatty Acid Oxidation during Dietary Restriction

Abstract: In the above article, the author's name, Mark K. Devries, was spelled incorrectly. We regret any inconvenience this may have caused.

Cited by 63 publications

References 0 publications

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

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